Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness.

Purpose: To clinically and biochemically characterize a rare autosomal recessive rod-cone dysfunction, with electroretinographic similarities to some forms of stationary night blindness (SNB), associated with biallelic variants in GUCY2D.

Methods: Six patients from five families with a history of longstanding night blindness, no fundus features suggestive of retinitis pigmentosa, and an unusual electroretinographic phenotype were ascertained. Clinical examination and genotyping were performed. Selected GUCY2D variants were tested for binding to and activation by guanylate cyclase-activating proteins (GCAPs) in HEK293 cells.

Results: The visual acuity was normal or moderately reduced (20/20-20/60) with three patients having a tritan defect on color vision testing. Retinal imaging showed central macular hypopigmentation with temporal vascular attenuation. Rod photoreceptor-mediated electroretinogram (ERG) components were undetectable or severely reduced in all but one case, and cone-mediated responses were variable. A high degree of ERG stability was demonstrated in three cases. Molecular analyses revealed biallelic variants of GUCY2D in all patients, four of which are clinically and biochemically characterized for the first time, to our knowledge. These allelic variants encoded retinal guanylyl/guanylate cyclase 1 (RetGC1) mutants whose enzymatic activities were significantly diminished due to drastically reduced affinity of RetGC1 for GCAPs.

Conclusions: The apparent lack of retinal degeneration, clinical features, predominant and severe rod photoreceptor involvement, and relatively high degree of ERG stability are similar to rare forms of SNB. Biallelic disease-causing variants in GUCY2D are usually associated with Leber's congenital amaurosis (LCA); however, this study illustrates the phenotypic variability of GUCY2D retinopathies in association with variants not biochemically dissimilar to those causing LCA and highlights the complexity of RetGC1 regulation in rod and cone photoreceptor function.